文章：

肿瘤进展中的Snail、Zeb 蛋白和 bHLH 因子：对抗上皮表型的联盟？

Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?

原文发布日期：2007-05-17

DOI: 10.1038/nrc2131

类型: Review Article

开放获取: 否

要点：

1. Local tumour invasion represents the first step of the metastatic cascade of carcinomas, and requires profound changes in the cell adhesion and migration properties of tumour cells that are reminiscent of developmental epithelial–mesenchymal transition (EMT). EMT is thought to be a dynamic and transient process, and as such is a manifestation of epithelial cell plasticity during tumour progression.
2. The loss of functional E-cadherin is a hallmark of EMT and carcinoma cell invasiveness. Transcriptional repression mediated by factors from the Snail (SNAI1 and SNAI2), Zeb (ZEB1 and ZEB2) and basic helix-loop-helix (bHLH: E47 and TWIST) families is a basic mechanism for the dynamic silencing of CDH1 (the gene that encodes E-cadherin).
3. Post-transcriptional modifications are emerging as a meaningful additional level of regulation of various repressors. The protein stability, nuclear localization and functional activity of SNAI1 seem to be controlled by a delicate balance between phosphorylation, zinc transporter proteins and interaction with lysyl-oxidase-like proteins.
4. Besides CDH1, additional direct and indirect target genes of Snail, ZEB and bHLH factors are being described that encode proteins involved in EMT as well as in cell proliferation, cell survival or angiogenesis, indicating that these factors have additional functions beyond the repression of CDH1 and the induction of EMT.
5. Snail and bHLH factors have recently been implicated in cell-survival and acquired resistance to genotoxic agents by cancer cells, providing new insights into the biological properties conferred by these factors, with potential clinical implications.
6. The expression patterns of Snail, ZEB and bHLH factors in different human carcinomas, together with functional studies, indicate that the various factors have different roles during tumour progression, with a more prominent role for SNAI1 in the induction of EMT in primary tumours, whereas the other factors are involved in maintaining the migratory phenotype.
7. Complex signalling networks from the tumour microenvironment, including hypoxia and transforming growth factor β (TGFβ), can coordinate the expression and/or function of Snail, ZEB and bHLH factors, and promote their interplay in orchestrating CDH1 repression and malignant tumour migration.

要点翻译：

1. 局部肿瘤侵袭是癌转移级联的第一步，需要肿瘤细胞在粘附和迁移特性上发生深刻变化，这一过程类似于发育过程中的上皮-间质转化（EMT）。EMT被认为是一个动态、瞬时的过程，因此是上皮细胞在肿瘤进展中可塑性的体现。
2. 功能性E-钙黏蛋白的缺失是EMT和癌细胞侵袭性的标志特征。由Snail（SNAI1和SNAI2）、Zeb（ZEB1和ZEB2）及碱性螺旋-环-螺旋（bHLH：E47和TWIST）家族因子介导的转录抑制，是CDH1（编码E-钙黏蛋白的基因）动态沉默的基本机制。
3. 转录后修饰正逐渐成为多种抑制因子调控的重要补充层面。SNAI1的蛋白稳定性、核定位及功能活性似乎受磷酸化、锌转运蛋白以及与赖氨酰氧化酶样蛋白相互作用的微妙平衡所调控。
4. 除CDH1外，Snail、ZEB和bHLH因子还有其他直接和间接靶基因，这些基因编码的蛋白质参与EMT、细胞增殖、细胞存活或血管生成，表明这些因子除了抑制CDH1和诱导EMT外，还具有其他功能。
5. 最近研究发现，Snail和bHLH因子与癌细胞存活及对基因毒性药物的获得性耐药有关，这为了解这些因子赋予的生物学特性提供了新视角，并具有潜在的临床意义。
6. Snail、ZEB和bHLH因子在不同人类癌症中的表达模式及功能研究表明，各类因子在肿瘤进展中扮演不同角色：SNAI1在原发性肿瘤EMT诱导中作用更为突出，而其他因子则参与维持迁移表型。
7. 来自肿瘤微环境的复杂信号网络（包括缺氧和转化生长因子β）可协调Snail、ZEB和bHLH因子的表达和/或功能，并促进它们协同调控CDH1抑制及恶性肿瘤迁移。

英文摘要：

The molecular mechanisms that underlie tumour progression are still poorly understood, but recently our knowledge of particular aspects of some of these processes has increased. Specifically, the identification of Snail, ZEB and some basic helix-loop-helix (bHLH) factors as inducers of epithelial–mesenchymal transition (EMT) and potent repressors of E-cadherin expression has opened new avenues of research with potential clinical implications.

摘要翻译： 

肿瘤进展的分子机制仍知之甚少，但最近我们对其中某些过程特定方面的认识有所增加。具体而言，发现Snail、ZEB及某些碱性螺旋-环-螺旋转录因子（bHLH）可诱导上皮-间质转化（EMT）并强力抑制E-钙黏蛋白表达，这为具有潜在临床意义的研究开辟了新途径。

原文链接：

Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?